Project III Brain derived neurotrophic factor (BDNF) plays a critical role in vertebrate nervous system development. Recently, a single nucleotide polymorphism (SNP) in the BDNF gene, a valine (Val) to methionine (Met) substitution in the prodomain (BDNFMet t), has been shown to result in impairments in humans in hippocampal dependent memory, decreased hippocampal volume, and susceptibility to neuropsychiatric disorders. Preliminary studies utilizing a novel transgenic knock-in mouse expressing the BDNFwet SNP have led us to hypothesize that the biological consequences of BDNFMet observed in the adult central nervous system are due to reduced BDNF availability during development. In this project, we propose to use the DNFMet knock-in mouse to establish the typical developmental trajectory of the hippocampus (He), prefrontal cortex (PFC), and amygdala (AMG), as a function of BDNF genotype. We will exploit tasks that are nearly identical to those proposed in human studies in Project I, to probe genotypic differences across development (Center Aim 1). In preliminary studies, we have determined that the BDNFMet genotype has significant effects on neuroanatomy of the He, PFC, and AMG, as well as their associated behaviors. In subsequent studies, environmental (stress, enrichment), as well as genetic (BDNF overexpression) interventions will be used to determine the precise impact of changing levels of BDNF across development. These studies will parallel work in Project 2, investigating the impact of early life adversity (orphanage) and subsequent placement into an adoptive home as a factor of genotype. The Specific Aims of Project III are to 1) determine the biological consequences of the variant BDNFMet on He, PFC, and AMG function across development, 2) determine the interaction between stress and genotype across development in BDNF mice through the assessment of He, PFC, and AMG function, and 3) Determine the effect of BDNF gain of function on He, PFC, and AMG function of the BDNFMet mouse across development.